Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.[CH2:9]([C:12]1[C:13]([Cl:24])=[CH:14][N:15]=[C:16]2[C:21]=1[N:20]=[C:19]([O:22][CH3:23])[CH:18]=[CH:17]2)[CH:10]=C.[CH3:25][OH:26]>ClCCl.O.O.O.[Os](=O)(=O)=O.[K]>[Cl:24][C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:12]=1[CH2:9][CH:10]([OH:5])[CH2:25][OH:26])=[N:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2
Reactant: CO
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCc1c(Cl)cnc2ccc(OC)nc12
Agent: O=[Os](=O)=O
Agent: [K]
Solvent: O
Solvent: ClCCl
Product: COc1ccc2ncc(Cl)c(CC(O)CO)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
N-Methylmorpholine-N-oxide (0.76 g, 64.0 mmol, 1.5 eq) is added at room temperature to a stirred solution of 8-allyl-7-chloro-2-methoxy-[1,5]naphthyridine (1.0 g, 4.26 mmol, 1.0 eq) in dichloromethane (40 mL) and water (4 mL), followed by potassium osmium(VI) oxide dihydrate (80 mg, 0.23 mmol, 0.05 eq). After 16 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×20 mL) and a saturated sodium sulfite aqueous solution (20 mL). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 40:1, v/v) to afford 3-(3-chloro-6-methoxy-[1,5]naphthyridin-4-yl)-propane-1,2-diol as a light yellow solid (1.1 g, 96% yield).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[Br:10][C:11]1[CH:12]=[C:13]([SH:17])[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:10][C:11]1[CH:12]=[C:13]([S:17][CH2:3][CH2:4][N:5]2[CH2:9][CH2:8][CH2:7][CH2:6]2)[CH:14]=[CH:15][CH:16]=1
Reactant: ClCCN1CCCC1
Reactant: Sc1cccc(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1cccc(SCCN2CCCC2)c1
Temperature: 25 °C
Yield: 31.4 %

Procedure:
1-(2-chloroethyl)pyrrolidine hydrochloride (1.0 equiv., 8.82 mmol) and 3-bromothiophenol (1.5 equiv., 13.23 mmol) were dissolved in acetonitrile (100 mL). Potassium carbonate (10.0 equiv., 88.2 mmol) was added to the reaction while stirring. The reaction was kept in oil bath at 80° C. to reflux for 18 h. The reaction was then cooled to room temperature and filtered to remove excess inorganics, and the organics were extracted with saturated NaHCO3 and brine. The organics were dried over Na2SO4 then concentrated under reduced pressure. The resulting crude oil was purified by flash chromatography using 4:6 EtOAc/hexanes. The fractions were concentrated to afford product as a yellow oil (792.3 mg, 32% yield). Rf=0.75 MS (ES+): m/z=287 LC retention time: 1.81 min.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH2:20][CH2:19][CH2:18][C:17]=3[CH:22]=2)=[C:11]([CH:23]([OH:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:10]([C:30]([F:33])([F:32])[F:31])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl(O)(=O)(=O)=O>C(OC(C)(C)C)(=O)C>[CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH2:20][CH2:19][CH2:18][C:17]=3[CH:22]=2)=[C:11]([CH:23]([O:29][C:2]([CH3:7])([CH3:3])[CH3:1])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:10]([C:30]([F:32])([F:31])[F:33])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(O)c1c(C(F)(F)F)nn(Cc2ccccc2)c1-c1ccc2c(c1)CCCO2
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: CCOC(=O)C(OC(C)(C)C)c1c(C(F)(F)F)nn(Cc2ccccc2)c1-c1ccc2c(c1)CCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.6 %

Procedure:
To a solution of ethyl 2-[1-benzyl-5-(3,4-dihydro-2H-1-benzopyran-6-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-hydroxyacetate (49f) (70 mg, 0.152 mmol) in tert-butyl acetate (2.9 mL) at 0° C. was added perchloric acid (0.347 mL). The mixture was stirred for 1 hour at room temperature before being slowly quenched with a saturated solution of potassium carbonate (10 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×10 mL). The organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (cyclohexane/ethyl acetate 75/25) to provide the desired ether (49g) (22 mg, 0.04 mmol, 28%) as a clear yellow oil.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:21])[N:8]([C:10]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:20])[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[H][H].[Br:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[C:29]([F:35])[CH:28]=1>CN(C=O)C.O>[Br:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:6]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9][N:8]([C:10]3[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:11]=3[Cl:20])[C:7]2=[O:21])=[C:29]([F:35])[CH:28]=1
Reactant: [H][H]
Reactant: Fc1cc(Br)ccc1CBr
Reactant: CCCCc1nn(-c2cc(C(=O)OC)ccc2Cl)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nn(-c2cc(C(=O)OC)ccc2Cl)c(=O)n1Cc1ccc(Br)cc1F
Temperature: 50 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
A mixture of 789 mg (2.55 mmole) of 5-n-butyl-2-[2-chloro-5-(methoxycarbonyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step C), 122.4 mg (3.06 mmole) of sodium hydride (60% in oil), and 2 mL of dry DMF was stirred at 50° C. for 2.5 hours, during which time hydrogen was evolved. A solution of 820 mg (3.06 mmole) of 4-bromo-2-fluorobenzyl bromide in DMF was added, and the mixture was stirred at 50° C. overnight. The cooled reaction mixture was diluted with H2O and extracted twice with ethyl acetate. The combined organic phase was washed with H2O and brine and then dried over Na2SO4. The filtered solution was concentrated, and the residue was flash chromatographed on 250 cc of silica gel packed in hexane (gradient elution with 6:1 to 5:1 hexane-EtOAc; some unreacted starting material was recovered by further elution with 95:5 CH2Cl2 --MeOH), yielding 503 mg (40%) of the title compound as an orange gum (TLC in 4:1 hexane-EtOAc), mass spectrum (FAB) m/e 496, 498 (M+1)+ .
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([S:21][CH3:22])[C:10]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:23])[CH:3]=1.[NH3:24]>CO>[I:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([C:10]2[C:9]([S:21][CH3:22])=[N:8][N:7]3[C:2]([NH2:24])=[CH:3][C:4]([CH3:23])=[N:5][C:6]=23)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccc(I)cc1
Reactant: N
Solvent: CO
Product: CSc1nn2c(N)cc(C)nc2c1S(=O)(=O)c1ccc(I)cc1

Procedure:
In an analogous manner to that described in Example 4), from 7-chloro-3-(4-iodo-benzenesulphonyl)-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine and NH3 in MeOH there was obtained 3-(4-iodo-benzenesulphonyl)-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine-7-ylamine as colorless crystals, m.p.>230°.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH:23]=[O:24])=[CH:17][C:15]=2[N:16]=1.[CH2:25](O)[CH2:26][OH:27]>C1C=CC=CC=1>[O:24]1[CH2:25][CH2:26][O:27][CH:23]1[CH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:14]2[O:13][C:12]([CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[N:16][C:15]=2[CH:17]=1
Reactant: OCCO
Reactant: O=CCCc1ccc2oc(Cc3ccc4ccccc4c3)nc2c1
Solvent: c1ccccc1
Product: c1ccc2cc(Cc3nc4cc(CCC5OCCO5)ccc4o3)ccc2c1
Reaction time: 3 h
Yield: 89.3 %

Procedure:
A mixture of 3-[2-(2-naphthylmethyl)benzoxazol-5-yl]propionaldehyde (2.9 g), ethylene glycol (0.685 g), P-toluenesulfonic acid monohydrate (0.175 g) and benzene (50 ml) was stirred for 3 hours under reflux. The reaction mixture was successively washed with aqueous solution of sodium hydrogencarbonate and water, and dried over magnesium sulfate (MgSO4). The solvent was distilled off, whereby 5-[2-(1,3-dioxolan-2-yl)ethyl]-2-(2-naphthylmethyl)benzoxazole (2.95 g, 89%) was obtained. Recrystallization from dichloromethane-isopropyl ether gave colorless prisms. Melting point: 85°-86° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].C(Cl)(Cl)[Cl:21]>ClCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([Cl:21])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccccc3c2c1C
Reactant: ClC(Cl)Cl
Agent: ClCl
Product: CCOC(=O)c1ncc2[nH]c3ccc(Cl)cc3c2c1C
Reaction time: 3 h

Procedure:
1 g of 4-methyl-β-carbolin-3-carboxylic acid ethyl ester is dissolved in 120 ml of chloroform saturated at 0° C. with chlorine gas and stirred for 3 hours while cooling with ice. The excess chlorine and part of the chloroform are then distilled with suction in vacuo, the crystalline precipitate is filtered off, suspended in 50 ml of ethyl acetate, and aqueous ammonia (5%, 10 ml) is added thereto. After 10 minutes, the crystalline product had dissolved. After separating off the aqueous phase and washing the organic phase with water, the residue is dried with sodium sulphate, filtered, and the solvent is distilled off in vacuo. The residue is crystallized from ethyl acetate. 0.73 g of 6-chloro-4-methyl-β-carbolin-3-carboxylic acid ethyl ester of melting point 225°-228° C. is obtained.
Reaction SMILES: Cl.Cl.[CH2:3]([C@:5]1([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]2)=[O:12])[CH2:9][CH2:8][C@H:7]([NH2:10])[CH2:6]1)[CH3:4].[CH3:29][CH:30]1[C:35](=O)[CH2:34][CH2:33][O:32][CH2:31]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:3]([C@:5]1([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]2)=[O:12])[CH2:9][CH2:8][C@H:7]([NH:10][CH:35]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[CH3:29])[CH2:6]1)[CH3:4]
Reactant: CC[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@H](N)C1
Reactant: CC1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@H](NC2CCOCC2C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
To a solution of (1S,3S)-3-ethyl-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentanamine dihydrochloride (100 mg, 0.20 mmol), 3-methyltetrahydro-4H-pyran-4-one (96 mg, 0.71 mmol), and triethylamine (0.11 mL, 0.79 mmol) in methylene chloride (3 mL) was added sodium triacetoxyborohydride (96 mg, 0.45 mmol). After being stirred at room temperature overnight, the reaction was quenched with saturated NaHCO3 and extracted with methylene chloride three times. The combined organics were dried (MgSO4), filtered, concentrated, purified by flash column chromatography (NH4OH/MeOH/EtOAc) to yield the desired product (38 mg, 40%). MS calculated for C24H35F3N4O2: (M+H) 469.3; found 469.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][CH2:7][C:8]#[C:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.[Br:25][C:26]1[CH:27]=[C:28]([C:31](O)=[O:32])[NH:29][CH:30]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[Br:25][C:26]1[CH:27]=[C:28]([C:31]([N:6]([CH2:5][C:4]2[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:3]=2[O:2][CH3:1])[CH2:7][C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[O:32])[NH:29][CH:30]=1
Reactant: COc1ccc(CNCC#Cc2ccc([N+](=O)[O-])cc2)c(OC)c1
Reactant: O=C(O)c1cc(Br)c[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(CC#Cc2ccc([N+](=O)[O-])cc2)C(=O)c2cc(Br)c[nH]2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 23B (1 g, 3.07 mmol) in anhydrous N,N-dimethylformamide (25 mL) was added 4-bromo-1H-pyrrole-2-carboxylic acid (0.67 g, 3.53 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (0.77 g, 4 mmol), 1-hydroxybenzotriazole hydrate (0.61 g, 4 mmol) and triethylamine (0.4 g, 4 mmol). The reaction was stirred at room temperature overnight, and partitioned between ethyl acetate and brine. The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude material was purified flash chromatography (20% ethyl acetate in hexane) to afford the title compound. LC-MS (ESI): m/z 500, 498 (M+H), RT: 2.37 min; 1H NMR (400 MHz, dimethylsulfoxide-d6): δ 3.75 (s, 3H), 3.78 (s, 3H), 4.51 (s, 2H), 4.77 (s, 2H), 6.53 (dd, J=6.4, 2.0 Hz, 1H), 6.60 (d, J=2.0 Hz, 1H), 7.09 (dd, J=1.2, 1.6 Hz, 1H), 7.15 (d, J=8.0 Hz, 1H), 7.60 (d, J=8.8 Hz, 2H), 8.21 (d, J=9.2 Hz, 2H), 12.02 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[OH-].[Na+].I[CH2:34][CH:35]([OH:38])[CH2:36][OH:37].CN(C)P(N(C)C)(N(C)C)=O>O.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH2:34][CH:35]([OH:38])[CH2:36][OH:37])=[O:27])=[CH:29][CH:30]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Reactant: OCC(O)CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: O=C(OCC(O)CO)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1

Procedure:
A solution of 7.34 g. of 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoic acid, 4.80 g. of 25% aqueous sodium hydroxide, and 12.6 g. of 3-iodo-1,2-propanediol in 50 ml. of hexamethylphosphoramide is stirred for 24 hours at ambient temperature, diluted with 100 ml. of ether and stirred for 5 days at ambient temperature. The mixture is treated with water and extracted with ether. The dried extracts are evaporated to yield 2,3-dihydroxypropyl 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:12]N(C)C)=O)=[CH:5][CH:4]=1.Cl.[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=[NH:31])=[CH:28][CH:27]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]2[N:32]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[C:11]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)=[CH:12][N:31]=2)=[CH:28][CH:27]=1
Reactant: COc1ccc(C(=O)C(=CN(C)C)c2ccc(OC)cc2)cc1
Reactant: N=C(N)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cnc(-c3ccc(Cl)cc3)nc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 9.34 g. of (4-methoxyphenyl)-[1-(4-methoxyphenyl)-2-dimethylaminovinyl]ketone, 5.73 g. of 4-chlorobenzamidine hydrochloride, and 6.73 g. of potassium t-butoxide in 200 ml. of toluene was allowed to reflux for 2.5 hours and then stirred overnight at room temperature. The suspension was extracted twice each with 200 ml. of water. The combined water extracts were back-extracted with 100 ml. of toluene. The combined toluene solutions were washed with 100 ml. of a saturated sodium chloride solution. The organic solution was then dried over sodium sulfate and evaporated in vacuo. The residue was purified by chromatography over silica gel. The appropriate fractions were evaporated to dryness and crystallized from Skelly B to provide 3.97 g. of the desired title product, m.p. about 151°-153° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:20][CH2:19][C@@H:18]([C:21]([NH:23][CH3:24])=[O:22])[N:17]2C(OC(C)(C)C)=O)=[CH:12][CH:11]=1.C([Cl:35])(C)=O>C(OCC)(=O)C.CO>[ClH:35].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[NH:17][C@H:18]([C:21]([NH:23][CH3:24])=[O:22])[CH2:19][CH2:20]2)=[CH:12][CH:11]=1
Reactant: CNC(=O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1C(=O)OC(C)(C)C
Reactant: CC(=O)Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CNC(=O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To a solution of 1,1-dimethylethyl (2R,5S)-2-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-5-[(methylamino)carbonyl]-1-pyrrolidinecarboxylate (D96, 40 mg, 0.09 mmol) in ethyl acetate (0.9 ml) and methanol (0.1 ml) at 0° C. was added AcCl (40 μl, 0.56 mmol) and the mixture was stirred for two hours at room temperature. The solvent was removed under nitrogen flow and the residue triturated with Et2O. The solvent was removed to afford the title compound as a white solid (28 mg, 85%). Rt (HPLC): 3.74 min; MS: (ES/+) m/z: 329-[MH+] C19H21FN2O2 requires 328; 1H NMR (500 MHz, DMSO-d6) δ (ppm): 10.03-10.78 (br.s, 1H); 8.56 (q, 1H); 7.95-8.46 (br.s, 1H); 7.55 (dt, 1H); 7.49 (d, 2H); 7.39-7.46 (m, 1H); 7.20-7.29 (m, 2H); 7.09 (d, 2H); 5.16 (s, 2H); 4.58 (dd, 1H); 4.28 (dd, 1H); 2.70 (d, 3H); 2.21-2.37 (m, 2H); 1.98-2.17 (m, 2H).
Reaction SMILES: [N+](=[CH:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:23])[CH:20]=[N+]=[N-])=[CH:11][CH:10]=1)=[N-].[Cl-:25].[Na+].[ClH:27].O>CO>[Cl:25][CH2:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:23])[CH2:20][Cl:27])=[CH:11][CH:10]=1
Reactant: Cl
Reactant: [N-]=[N+]=CC(=O)CCCCc1ccc(CCCCC(=O)C=[N+]=[N-])cc1
Reactant: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(CCl)CCCCc1ccc(CCCCC(=O)CCl)cc1
Reaction time: 4 h
Yield: 53 %

Procedure:
A solution of about 27 millimoles of 1,4-bis-(6'-diazo-5'-oxohexyl)-benzene (prepared from 7.6 g of p-phenylene-δ,δ-divaleryl chloride) in 70 ml of methanol is added dropwise to a mixture of 58 ml of 5 M aqueous sodium chloride solution and 58 ml of 2 N aqueous hydrochloric acid solution. During the dropwise addition, the material in the reaction vessel must be cooled and stirred vigorously. After the addition, and when nitrogen evolution has ceased, stirring is continued for 4 hours at room temperature. 200 ml of water are added to the solution and the mixture is extracted with chloroform. The combined chloroform phases are washed with 200 ml of water and the pale yellow solution is dried over sodium sulfate. It is then filtered and concentrated on a rotary evaporator. The yellow solid residue is chromatographed on a silica gel column (length 50 cm, diameter 5 cm), using chloroform as the mobile phase. The bis-chloroketone migrates fastest. After concentrating the fractions, colorless 1,4-bis-(6'-chloro- 5'-oxohexyl)-benzene is obtained, and this is recrystallized from cyclohexane. The substance is obtained in 53% yield (4.9 g); melting point 86°-87° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[O-:3].[Yb+3:5].[CH3:6][CH:7]([CH3:9])[O-:8].[CH3:10][CH:11]([CH3:13])[O-:12].[CH3:14][O:15][CH2:16][CH2:17]O>>[CH3:1][CH:2]([CH3:4])[O-:3].[Yb+3:5].[CH3:6][CH:7]([CH3:9])[O-:8].[CH3:10][CH:11]([CH3:13])[O-:12].[CH3:14][O:15][CH:16]([CH3:17])[O-:3].[Yb+3:5].[CH3:14][O:15][CH:16]([CH3:17])[O-:3].[CH3:14][O:15][CH:16]([CH3:17])[O-:3]
Reactant: COCCO
Agent: CC(C)[O-]
Agent: [Yb+3]
Product: COC(C)[O-]

Procedure:
Ytterbium isopropoxide was synthesized using the method of 20 Brown et al. A flask containing 4.85 g (15 mmole) of ytterbium isopropoxide was reacted with 50 ml of 2-methoxyethanol under an atmosphere. After refluxing for approximately 1 hour, two-thirds of the solution (isopropanol and 2-methoxyethanol) was removed by distillation. The flask was allowed to cool, and 20 ml of 2-methoxyethanol was added. The flask was refluxed for 1 hour, and ⅔ of the solution was then removed by distillation. This process of dilution, reflux, and distillation was repeated for a total of three cycles to ensure the complete exchange of the methoxyethoxide ligand for the isopropoxide ligand. It was estimated that this occurs when the boiling point of the solution reaches 124° C. The final concentration of the solution was adjusted to obtain a 0.5 M solution of ytterbium methoxyethoxide in 2-methoxyethanol. Coating solutions were prepared by reacting 1 part of a 1.0 molar solution of water in 2-methoxyethanol with 4 parts of the 0.5 M ytterbium methoxyethoxide solution.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[CH:13]1[CH:18]=[C:17]2[C:19]([C:22]([C:24](Cl)=[O:25])=[O:23])=[CH:20][NH:21][C:16]2=[CH:15][CH:14]=1>O>[NH:21]1[C:16]2[C:17](=[CH:18][CH:13]=[CH:14][CH:15]=2)[C:19]([C:22](=[O:23])[C:24]([N:1]2[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]2)=[O:25])=[CH:20]1
Reactant: OC1CCNC1
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(C(=O)N1CCC(O)C1)c1c[nH]c2ccccc12

Procedure:
--A solution of 1.25 g. (0.014 mole) of 3-pyrrolidinol and 3.0 g. of sodium carbonate in 35 ml. of water was treated all at once with 3 g. (0.014 mole) of indole-3-glyoxyloyl chloride and the mixture stirred at room temperature for 24 hours. The product was isolated by filtration and recrystallized from absolute alcohol. The yield was 2.6 g. (70%) and the material melted at 216°-218° C.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:26][C:27]1[O:31][N:30]=[C:29]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:28]=1.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH2:20][CH2:21][O:22][CH3:23])[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:33]([NH:32][C:29]2[CH:28]=[C:27]([CH3:26])[O:31][N:30]=2)=[O:34])=[CH:25][CH:24]=1)#[N:18]
Reactant: COCCOc1cc2nccc(Oc3ccc(N)cc3)c2cc1C#N
Reactant: Cc1cc(NC(=O)Oc2ccccc2)no1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)on4)cc3)c2cc1C#N
Yield: 87.6 %

Procedure:
The 4-(4-aminophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (100 mg) synthesized in Production Example 10 and phenyl N-(5-methylisoxazol-3-yl)carbamate (72 mg) were added to toluene (5 ml), and then diisopropylethylamine (0.50 ml) was added and the mixture was heated to reflux for 2 hours. After cooling, the precipitated crystals were filtered and washed with an ethyl acetate/toluene (1/1) mixed solvent to obtain the title compound (120 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:8][C:7]=1[OH:19].COC1C=C(C2C=CC=CC=2)C=CC=1>>[Cl:12][C:10]1[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][C:7]2[O:19][CH2:2][CH2:3][CH2:4][CH2:5][C:6]=2[CH:11]=1
Reactant: Oc1cc(C2CCCCC2)c(Cl)cc1CCCCBr
Agent: COc1cccc(-c2ccccc2)c1
Product: Clc1cc2c(cc1-c1ccccc1)OCCCC2

Procedure:
The 1-bromo-4-(5-chloro-2-hydroxy-4-biphenyl)-butane used as the starting material is produced in manner analogous to that employed for 1-bromo-4-(5-chloro-4-cyclohexyl-2-hydroxy-phenyl)-butane from 3-methoxy-biphenyl.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:10]([N+:11]([O-])=O)=[C:9]([Cl:14])[C:8]([N+:15]([O-])=O)=[CH:7][C:4]=1[C:5]#[N:6].[OH-].[Na+]>>[Cl:2][C:3]1[C:10]([NH2:11])=[C:9]([Cl:14])[C:8]([NH2:15])=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: N#Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1cc(N)c(Cl)c(N)c1Cl
Temperature: 25 °C

Procedure:
A solution of 330 g. (1.46 mole) of stannous chloride dihydrate in 807 ml. of concentrated hydrochloric acid is stirred and there is added 53.5 gm. (0.204 mole) of 2,4-dichloro-3,5-dinitrobenzonitrile. The temperature rises to 85° and is then allowed to cool to room temperature over a period of 2 hours. The mixture is cooled to 5° in an ice-bath and there is added, slowly, 50% sodium hydroxide until the mixture is strongly basic. The precipitate is removed by filtration. The filtrate is placed in a separatory funnel. The precipitate is extracted with three volumes of ethyl acetate. The combined ethyl acetate extracts are added to the aqueous filtrate and the resulting mixture shaken thoroughly for ten minutes. The phases are separated and the organic phase dried over magnesium sulfate. The drying agent is removed by filtration. The filtrate is evaporated to dryness in vacuo. The yellow solid is recrystallized from absolute ethanol to yield 33.7 g. (82%) of yellow needles melting at 189°-191°.